We are trying to understand the mechanism of action of morphine and related narcotic analgesics, with special reference to the mechanism by which these drugs produce tolerance and physical dependence. We have so far not been able to confirm reports that chronic morphine treatment of rats reduces the sensitivity of diaphragm to the action of insulin; it clearly increases the sensitivity of fat cells to the action of insulin. We are currently carrying out a detailed survey of the effects of chronic morphine treatment on the following parameters in a variety of peripheral tissues and brain areas: adenylyl cyclase, guanyl cyclase, cyclic nucleotide phosphodiesterase(s), protein kinase, and the tissue levels of cyclic AMP and cyclic GMP. We are also studying the effects of insulin and epinephrine on protein kinase in the rat diaphragm, with a view to determining how or if this enzyme is affected in the morphine-dependent rat. We are simultaneously using specific pharmacological agents to determine which neurotransmitters are involved in the centrally mediated effects of morphine on body temperature, and have already obtained evidence that in the cat (where the response to morphine is hyperthermia) dopamine and acetylcholine are probably involved. If tolerance develops to these effects, our hope is that we will be able to apply our knowledge of the mechanism of action of morphine in simpler peripheral systems to a better understanding of its central effects.